Liver transplantation (LTx) is now well-established as a means of restoring health in patients with liver failure, the 10th leading cause of death in the US. Although many advances have been made in the care and outcome of patients undergoing LTx, opportunities still exist to further optimize the health and quality of life in our patients. One such example is chronic renal insufficiency which occurs commonly among LTx recipients and causes significant morbidity and mortality. Post-LTx renal insufficiency is most commonly a result of long term exposure to calcineurin inhibitors, namely cyclosporine and tacrolimus, used to prevent and treat rejection. Calcineurin inhibitors cause intense vasoconstriction of renal vasculature, decreasing blood flow and function of the kidneys. Data to date attribute these effects to impaired vascular endothelial function and reduced production of vasodilators such as nitric oxide (NO). Once it is established, there is no effective treatment for calcineurin inhibitor-induced renal insufficiency. L-arginine, a precursor of NO, has been shown to reverse the effects of calcineurin inhibitors on the vascular system as well as kidneys in experimental animals. In this application, we hypothesize that L-arginine provides protection against calcineurin inhibitor nephrotoxicity in human LTx recipients. We will conduct a double-blinded trial in which twenty-four LTx recipients will be randomized to receive 9 g/day of L-arginine or placebo orally for 7 days between 14 and 21 days after LTx. We then will compare changes in renal plasma flow before and after the 7-day trial (Aim 1). Additionally, the effects of oral L-arginine on glomerular filtration rate, cardiac output, systemic vascular resistance, endothelial function, plasma arginine level and urinary cyclic-GMP will be assessed (Aim 2). Finally, we will evaluate the safety of L-arginine in LTx recipients (Aim 3). The significance of our research is that calcineurin inhibitor-induced renal insufficiency is a major source of morbidity and mortality among LTx recipients, that there is no established treatment for it, and that positive results in this study will lend support to a full scale, randomized trial to evaluate whether long-term arginine may prevent or treat calcineurin inhibitor nephrotoxicity. Such a study will be able to answer whether a simple amino acid supplement may prevent post-LTx chronic renal insufficiency, which will make a fundamental difference in morbidity, mortality and quality of life of our patients, who have undergone a life-changing procedure, namely liver transplantation. PUBLIC HEALTH RELEVANCE: Chronic renal insufficiency is a common and important health problem that causes morbidity and mortality among patients who have undergone liver transplantation. It is mainly caused by drugs (calcineurin inhibitors) that are used to prevent or treat rejection. Once established, there is no effective treatment. This research investigates whether L- arginine can reverse the effects of calcineurin inhibitors on the kidneys and thus prevent renal insufficiency in liver transplant recipients.